Continuous flow process for the polymerization of an alkylene oxide

ABSTRACT

A continuous-flow process for the polymerization of an alkylene oxide is provided that includes:
         (a) Mixing an alkylene oxide ( 1 ) with a monomer solvent ( 12 ), to form a monomer solution ( 121 ); wherein the monomer solvent is a polar aprotic solvent   (b) Forming a reaction mixture ( 3 ) by mixing the monomer solution with an anionic initiator ( 2 ) selected among the alkali or alkaline-earth alkoxides of general formula R-O-M, wherein,
           R is a straight, branched or cyclic alkyl chain, a heterocycle, a glycol or a combination of two or several of these,   O is oxygen, and   M is or includes at least an alkali, an alkaline-earth metal or salt thereof;   
           (c) Allowing the reaction mixture to react, thus forming a polymerized solution ( 5 ); and   (d) Separating the solvent ( 5   s ).

FIELD OF THE INVENTION

The present invention generally relates to the polymerization ofalkylene oxides, such as ethylene oxide, propylene oxide, or butyleneoxide. In particular, it concerns a particularly efficient continuousflow process for the polymerization of alkylene oxide carried out at lowtemperatures, such as room temperature, and moderate pressure, such as 1to 20 bar. The continuous flow process of the present invention is moreefficiently carried out in a micro-polymerization line, wherein mixingand temperature of the components is rapid and easy to control.

BACKGROUND OF THE INVENTION

Aliphatic polyethers are an important class of polymers used in manyapplications, ranging from pharmaceutical formulations to materialtechnology. Among these polyethers, macromolecules synthesized fromethylene oxide, propylene oxide, and butylene oxide are the most commonalkene oxides. Polyether-based polymers have unique properties arisingfrom their hydrophilic backbone. Aliphatic polyethers can be prepared ashomo- or heterobifunctional polymers with various end-chain functions,or can be incorporated in other macromolecular structures.

Several techniques for the polymerization of alkene oxides have beenreported in the literature. Anionic polymerization has been usedextensively. The anionic polymerization of alkene oxides usesnucleophiles as initiators. For example, low-molecular weightpoly(ethylene oxide) (4 kDa) is commonly obtained by reacting ethyleneoxide with water or alkali hydroxides as initiators. High-molecularweight poly(ethylene oxide) (50 kDa) architectures usually requirealkali alkoxides (mostly sodium or potassium) or other nucleophiles suchas hydrides or amines as initiators. Alkali alkoxides in polar solventssuch as tetrahydrofuran (THF) constitute a well-known and efficient typeof initiators for alkene oxide polymerization. Polymerization in bulkhas also been reported, although it comes with a higher polydispersity.Fast kinetics are reported with primary alkoxides, while bulkierinitiators tend to lower the reaction speed. Other additives such ascrown ethers may be added to enhance the polymerization kinetics. Hightemperatures of up to 250° C. and high pressures of up to 150 bar,however, are generally required to yield industrially acceptablepolymerization kinetics.

As an example, tetrahydropyranyl monoprotected ethylene glycol wasreported by Hiki and Kataoka (in Bioconjugate Chem. 2010, 21, 248-254)as an efficient pre-initiator. In situ deprotonation of thispre-initiator, followed by addition of ethylene oxide yieldsα-(tetrahydropyranyl-O),ω(OH)-heterobifunctional poly(ethylene glycol)with yields of up to 97%, polydispersity of 1.03 to 1.04, andconcordance of theoretical and experimental molar mass.Heterobifunctional polyethers with different chain-ends were preparedwith this pre-initiator, which allowed independent functionalization ortransformation of both chain-ends.

Most of the processes reported in the art for the polymerization ofalkene oxides rely on macroscopic batch reactors (internal dimensionstypically greater than 10⁴ μm, and internal volumes ranging from 10⁻³ Ito 10³ I, as described in, for example, CN102453253, CN102391494,CN103554472, CN103709391, CN103709393, CN103709389. Since alkene oxidesand, in particular, ethylene oxide are extremely reactive, highlyexplosive and toxic molecules, their handling in macroscopic batchreactors raises significant safety issues, especially when hightemperature and pressure conditions are required. Besides safety issues,conventional macroscopic batch reactors also come with inherentlimitations for heat exchange and mixing efficiency, which can accountfor poor reaction control, decrease in molecular weight and largermolecular weight distribution.

To overcome such limitations, continuous-flow methods were developed, asdescribed in DE2900167, DD142809, CN102099396, CN1390240, CN104829824,CN101367925. Continuous-flow methods have the advantages over batchmethods of more efficient heat exchanges and higher mixing efficiency.They also ensure a safer process with an enhanced control over thereaction conditions and homogeneity of the polymer thus produced.Continuous-flow reactors are composed of channels for the circulation ofchemicals. The internal diameter of such channels is typically of theorder of 250-800 μm in continuous-flow microreactors and is >1 mm incontinuous-flow mesoreactors. The polymerization conditions in thecontinuous-flow processes reported in the foregoing documents for theproduction of alkene oxides comprise temperatures ranging from 100 to250° C., pressures ranging from 0.2 to 15 MPa (=2 to 150 bar), andreaction times ranging from 0.5 to 3 h.

In particular, CN101367925, describes feeding into a continuous flowmesoreactor of internal diameter of 50-100 mm, three streams ofmaterials including a regulator, oxirane monomer, and an ammonia-calciumcatalyst, each in a solvent selected from n-hexane or n-heptane. Thethree materials are first blended at low temperature of −50 to −20° C.,and then reacted at a temperature of 20 to 40° C. for 20 to 40 min.

CN104829824 describes a continuous flow polymerization processcomprising (a) preparing a liquid catalyst by reacting an alkali base(KOH, NaOH or NaOR and KOR) and a pre-initiator (polyol or polyamine),and (b) reacting the thus prepared liquid catalyst with an alkene oxidein a continuous-flow microreactor equipped with a micro-mixer and aresidence time unit. Reaction temperatures ranging from 150 to 250° C.and pressures ranging from 20 to 150 bar were required to polymerizeethylene oxide within reaction times comprised between 20 and 1000 s(=0.3 to 17 min).

The present invention proposes a polymerization process of alkyleneoxides which is safe, has high yield, and can be carried out at moderateto low temperatures, pressures, and reaction times. These and otheradvantages of the present invention are described in continuation.

SUMMARY OF THE INVENTION

The present invention is defined by the attached independent claims. Thedependent claims define preferred embodiments. In particular, thepresent invention concerns a continuous-flow process for thepolymerization of an alkylene oxide comprising the following steps:

-   -   (a) mixing an alkylene oxide with a monomer solvent, to form a        monomer solution; wherein the monomer solvent is a polar aprotic        solvent, wherein the alkylene oxide is preferably selected among        ethylene oxide, propylene oxide or butylene oxide,    -   (b) forming a reaction mixture by mixing the monomer solution        with an anionic initiator selected among the alkali or        alkaline-earth alkoxides of general formula R-O-M, wherein        -   R is a straight, branched or cyclic alkyl chain, an            heterocycle, a glycol or a combination of two or several of            these,        -   O is oxygen, and        -   M is or comprises an alkali, an alkaline-earth metal or salt            thereof; and is preferably selected among lithium, sodium or            potassium, and        -   wherein the anionic initiator is preferably dissolved in a            solvent to form an initiator solution before mixing with the            monomer solution, preferably the initiator solvent is the            same as the monomer solvent,    -   (c) allowing the reaction mixture to react,        -   for a polymerization time, t, comprised between 1 s and 60            min, preferably between 20 s and 50 min, more preferably            between 30 s and 20 min,        -   at a polymerization temperature, T, comprised between 0 and            100° C., preferably between 20 and 50° C., more preferably            between 25 and 35° C. and        -   at a polymerization pressure, P, comprised between 1 and 20            bar, preferably between 1.5 and 10 bar, more preferably            between 2 and 5 bar, above atmospheric pressure,        -   thus forming a polymerized solution comprising a polymerized            alkylene oxide and a solvent; and    -   (d) separating the solvent from the polymerized alkylene oxide

In a preferred embodiment, the monomer solvent can have:

-   -   a donor number (DN) of at least 120 kJ/mol according to        Gutmann's thermodynamic scale and/or    -   an acceptor number (AN) of not more than 20 according to        Gutmann-Beckett's scale and/or    -   a dielectric constant (E) greater than 30.

For example, the monomer solvent can be one of dimethyl sulfoxide(DMSO), hexamethylphosphoramide (HMPA), tetraalkylureas, or cyclicalkylureas, preferably 1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone(DMPU) and pyridine.

The continuous-flow process of the present invention is preferablycarried out in a polymerization line, wherein step (a) is carried out ina solution reactor module), step (b) is carried out in a mixing reactormodule (103) in fluid communication with the first reactor module bymeans of a connecting tube, and wherein step (c) is carried out in apolymerization reactor module, preferably a tubular reactor forming aserpentine. For a more efficient control of the reaction, thecontinuous-flow process is preferably carried out in amicro-polymerization line, wherein the internal diameters of thesolution and mixing reactor modules are comprised between 100 μm and1000 μm, preferably between 200 and 800 μm and wherein the connectingtube and polymerization reactor module are capillary tubes of innerdiameter comprised between 50 and 700 μm, preferably between 100 and 500μm. For example, the total inner volume of the solution, mixing, andpolymerization reactor modules and connecting tubes can be comprisedbetween 1 and 10 ml, preferably between 2 and 6 ml

The molar ratio of monomer to initiator must be carefully controlled. Itis preferred that the monomer to initiator molar ratio be comprisedbetween 2000 and 20, preferably between 100 and 30, and more preferablybetween 50 and 40. The molar ratio is controlled, on the one hand, bythe flowrates of the monomer solution and initiator (solution) and, onthe other hand, on the monomer and initiator concentrations in theirrespective solutions.

For example, the following flowrates of the various components can beachieved with a micro-polymerization line:

-   -   The flow rate of the reaction mixture through the polymerization        reactor module can be comprised between 0.1 and 10 ml/min,        preferably between 0.3 and 1 ml/min; and/or    -   The flow rate of monomer solution into the mixing reactor module        can be comprised between 0.1 and 9 ml/min, preferably between        0.2 and 1 ml/min, and/or    -   The flow rate of initiator into the mixing reactor module can be        comprised between 0.1 and 1 ml/min, preferably between 0.2 and        0.5 ml/min

The alkylene oxide and initiator can be present in their respectivesolutions at the following concentrations:

-   -   The alkylene oxide can be present in the monomer solution at a        concentration comprised between 0.1 and 10 M, preferably between        1 and 5 M, and/or    -   The anionic initiator can be fed into the mixing reactor module        in a solvent, preferably the same as in step (a), at a        concentration comprised between 0.1 and 10 M, preferably between        1 and 5 M.

For optimizing the mixing efficacy of the components, the polymerizationline preferably comprises mixing devices. For example, the solution andmixing reactor modules can be equipped with a mixing device comprisingone or more of an arrow-head mixer, T-mixer, Y-mixer, cross-junctionmicromixer, or static micromixer, made of glass, stainless steel,polymeric material, or ceramics, or a combination of two or more of theforegoing materials.

The continuous-flow process of the present invention can compriseadditional steps between steps (c) and (d) including,

-   -   (c1) functionalizing one or both ends of polymer chains of the        polymerized solution by addition in a functionalization reactor        module of one or two functionalization agents (6) to the        reaction mixture as it polymerizes, or to the polymerized        solution, and/or    -   (c2) terminating the polymerization by addition in a terminating        reactor module of a termination agent to the polymerized        solution after the time, t, and/or    -   (c3) monitoring the polymerization of the reaction mixture by        means of one or more in line analysis units, preferably        comprising at least one spectroscopic analysis unit,    -   (c4) a precipitation step for forming in a precipitation unit        two distinct phases in the polymerized solution, with a liquid        phase, formed by solvent(s), and a solid phase formed by the        alkylene oxide polymer.

After or within the separation unit, an extraction step can be used torecover and recycle the solvent.

BRIEF DESCRIPTION OF THE FIGURES

Various embodiments of the present invention are illustrated in theattached Figures.

FIG. 1: shows a continuous reactor device suitable for carrying out theprocess of the present invention.

FIG. 2: shows an alternative continuous reactor device suitable forcarrying out the process of the present invention.

FIG. 3: shows polymerization times for different monomer solvents.

FIG. 4: illustrates the effects of donor and acceptor number on thereactivity of the reaction mixture.

DETAILED DESCRIPTION OF THE INVENTION Polymerization Process andPolymerization Line

As can be seen in FIG. 1, the various steps of a continuous-flow processfor the polymerization of an alkylene oxide according to the presentinvention can be carried out in a polymerization line. Thepolymerization process comprises a first step (a) of mixing an alkyleneoxide (1) with a monomer solvent (12), to form a monomer solution (121).The monomer solvent must be a polar aprotic solvent. This step can becarried out in a solution reactor module (101), preferably provided witha mixing device (9).

In a second step (b), an anionic initiator (2) is mixed with the monomersolution to form a reaction mixture (3). The anionic initiator is analkali or alkaline-earth alkoxide of general formula R-O-M, wherein,

-   -   R is a straight, branched or cyclic alkyl chain, a heterocycle,        a glycol or a combination of two or several of these,    -   O is oxygen and    -   M is or comprises an alkali, an alkaline-earth metal or salt        thereof.

The anionic initiator is preferably added to the monomer solution in aliquid form. The anionic initiator can either be liquid at the pressureand temperature of the system (cf. FIG. 1), or dissolved in an initiatorsolvent (22) to form an initiator solution (222) (cf. FIG. 2). Theinitiator solvent is preferably the same as, or is at least soluble inthe monomer solvent. The initiator solution can be prepared in aninitiator reactor module (102). Pumps (8), preferably volumetric pumpscan be used for feeding the monomer solution (121) and the anionicinitiator (2) or initiator solution (222) into a mixing reactor module(103) to form the reaction mixture (3). For example, piston pumps can beused. The volumetric control of the feeding of monomer solution andanionic monomer is important to control the monomer to initiator ratio.The monomer to initiator ratio is preferably comprised between 2000 and20, more preferably between 100 and 30, and most preferably between 50and 40.

The mixing reactor module (103) is also preferably provided with amixing device (9). The mixing device can be selected among one or moreof an arrow-head mixer, T-mixer, Y-mixer, cross-junction micromixer, orstatic micromixer. The mixer devices can be made of glass, stainlesssteel, polymeric material, or ceramics, or a combination of two or moreof the foregoing materials. The quality of mixing of the variouscomponents is very important in the continuous process of the presentinvention, as it influences the polymerization kinetics, yield, andhomogeneity (e.g., narrower molecular weight distribution).

The reaction mixture is allowed in a third step (c) to react for apolymerization time, t, at a polymerization temperature, T, and at apolymerization pressure, P, to form a polymerized solution (5): Thepolymerization solution is not necessarily a true solution and can be asuspension or simply a mixture of solvent and polymerized alkylene oxideinstead. The polymerization reaction can be carried out in apolymerization reactor module (104), which is preferably a tubularreactor forming a serpentine in fluid communication with the mixingreactor module (103). The flow rate of the reaction mixture (3) from themixing reactor module to the polymerization reactor module can becontrolled by a valve or a pump. The polymerization time, temperature,and pressure required for completing polymerization strongly depend onthe monomer solvent used, as can be seen in FIG. 3, which will bediscussed more in detail below.

By selecting an appropriate monomer solvent (21), polymerization timescomprised between 1 s and 60 min can be reached, at a temperaturecomprised between 0 and 100° C., and at a pressure comprised between 1and 20 bar above atmospheric pressure. Preferably, the polymerizationtime is comprised between 20 s and 50 min, more preferably between 30 sand 20 min. The temperature may be comprised between 20 and 50° C.,preferably between 25 and 35° C. The polymerization pressure, P, may becomprised between 1.5 and 10 bar, preferably between 2 and 5 bar aboveatmospheric pressure.

After the polymerization reaction is completed, a polymerized solution(5) is collected at a step (e) in a polymer vessel (105). Thepolymerized alkylene oxide (5 p) is then separated from the solvent (5s) in a separation unit (105 p). The polymerized alkylene oxide (5 p) isgenerally a solid in suspension in a solvent. The separation unit canthen be simply a decantation vessel. The separation unit preferablycomprises separation means, such as a filter. In order to accelerate theseparation step, filtration can be carried out under pressure orcentrifugal forces. If the polymerized alkylene oxide (5 p) is dissolvedin the solvent (5 s), the polymerized alkylene oxide (5 p) can be madeto precipitate before reaching the separation unit. If the same solventas the monomer solvent has been used throughout the process, the solvent(5 s) of the polymerized solution is monomer solvent (21). Thisembodiment is preferred, because the monomer solvent can be recycledafter separation to form new solutions. If different solvents are usedto form the initiator solution, or a functionalization or terminationsolution, then the solvent (5 s) is a mixture of solvents, which needsbe separated again prior to re-use.

The various reactor modules (101-104), vessel (105) and separation unit(105 p) are in fluid communication with one another has illustrated inFIG. 1, by a series of connecting tubes. The connecting tubes may beprovided with pumps (8) or valves for allowing the control of flowthrough one or more connecting tubes.

The continuous flow process of the present invention allows thefunctionalization of one or more of the two ends of the poly(alkyleneoxide) chains formed in the polymerization reactor module (104). Asillustrated in FIG. 2, a functionalization reactor module (106) can beprovided for feeding one or more (generally one or two)functionalization agents (6) to the reaction mixture as it polymerizesin the polymerization reactor module (104), or to the polymerizedsolution in the polymer vessel (105). Any functionalization agentsuitable for reacting with one or both chain ends of the polymer can beused in the continuous flow process of the present invention. Examplesof functionalization agents (6) include but are not limited toaziridines, alkyl sulfonates, cyclic sulfonates (sultones), alkyltriflates and anhydrides. A person of ordinary skill in the art knowsthe advantages associated with functionalization and can select the mostappropriate functionalization agents to a particular application. Thefunctionalization agent(s) may be fed directly into the polymerizingreaction mixture or into the polymerized solution if it (they) areliquid. Alternatively, the functionalization agent(s) can be dissolvedin a solvent, compatible with (i.e. soluble in), or the same as themonomer solvent.

As shown in FIG. 2, the polymerization line may also comprise aterminating reactor module (107) for feeding a termination agent (7) tothe polymerizing reaction mixture at or downstream from thepolymerization reactor module (104), for terminating the polymerization.The use of a termination agent allows the control of the molecularweight of the polymerized alkylene oxide. Termination agents may beacids, such as acetic acid, formic acid, aqueous hydrochloric acid, oraqueous ammonium chloride.

The polymerization line may be equipped with one or more in lineanalysis units for monitoring the polymerization of the reactionmixture. Spectroscopic analysis units are preferred such as an infraredspectroscopy unit (e.g., FTIR). Similarly, the polymerization line maybe equipped with additional operations units such as,

-   -   a precipitation unit for forming two distinct phases in the        polymerized solution (5), with a liquid phase, formed by the        solvent(s) (5 s), and a solid phase formed by the alkylene oxide        polymer (5 p) in view of their separation in the separation unit        (105 p),    -   an extraction unit for recycling solvents.

Alkylene Oxide Monomer and Anionic Initiator

The alkylene oxide monomer used in the process of the present inventionis preferably selected among ethylene oxide, propylene oxide or butyleneoxide. The alkylene oxide monomer may in some embodiments be admixedwith a comonomer such as a lactide, caprolactone or a different alkeneoxide. The alkylene oxide monomer is present in the monomer solution ata concentration preferably comprised between 0.1 and 10 M, morepreferably between 1 and 5 M.

As explained supra, the anionic initiator suitable for the presentinvention is selected among the alkali or alkaline-earth alkoxides ofgeneral formula R-O-M, wherein,

-   -   R is a straight, branched or cyclic alkyl chain, an heterocycle,        a glycol or a combination of two or several of these,    -   O is oxygen and    -   M is or comprises an alkali, an alkaline-earth metal or salt        thereof.

M is preferably selected among lithium, sodium or potassium. In someembodiments, the anionic initiator may include an alkali tert-butoxideor a monotetrahydropyranylated ethylene glycol potassium salt. Forexample, the anionic initiator can be potassium2-(tetrahydro-2H-pyran-2-yloxy)ethoxide (=THPOCH₂CH₂OK) or potassiumtert-butoxide.

The alkylene oxide may be present in the monomer solution at aconcentration comprised between 0.1 and 10 M, preferably between 1 and 5M. If, as illustrated in FIG. 2, the anionic initiator is fed into themixing reactor module as an initiator solution (222) dissolved in aninitiator solvent (22), preferably the same as the monomer solvent (21),then the anionic initiator can be present in the initiator solvent at aconcentration comprised between 0.1 and 10 M, preferably between 1 and 5M.

Monomer Solvent

As shown in FIG. 3, the choice of the monomer solvent has a surprisinglydominant influence on the kinetics of polymerization of alkylene oxidesaccording to the present invention. The kinetics of ethylene oxidepolymerization in various solvents was studied. A 50 ml Schlenk flaskwas charged with potassium tert-butoxide as initiator (2). Dry anddegassed solvents as listed in Table 1 and liquid ethylene oxide (1)were successively added. The polymerization reactions were performed inNMR tubes and a NMR spectrum was recorded every 30 min over 15 h at 25°C. for each solvent. The ethylene oxide to initiator molar ratio wasfixed at 44, and the concentration of the monomer was 4 M. Theconversions plotted in FIG. 3 as a function of time were determined bymonitoring the disappearance of a typical signal of ethylene oxide (atca. 2.5 ppm), and the appearance of a typical signal of poly(ethyleneglycol) (at ca. 3.6 ppm).

TABLE 1 solvents tested and plotted in FIG. 3, with values of donornumber (DN) and acceptor number (AN) DN DN AN Ref Solvent name[kcal/mol] [kJ/mol] [—] C6D6 CEX Benzene-d6 (Hexadeuterobenzene) 0.4 1.78.2 d8-THF CEX Tetrahydrofuran-d8 (Octadeuterotetrahydrofuran) 20.0 84.08.0 CD2Cl2 CEX Dichloromethane-d2 (Dideuteromethylenechloride) 1.0 4.220.4 CD3CN CEX Acetonitrile-d3 (Trideuteroacetonitrile) 14.1 59 18.9d7-DMF CEX N,N-Dimethylformamide-d7 (Heptadeutero-N,N-dimethylformamide)26.6 111.0 14.2 d6-DMSO INV Dimethyl sulfoxide-d6 (Hexadeuterodimethylsulfoxide) 29.8 125.0 19.3 CEX = comparative example; INV = according tothe present invention

It can be seen in FIG. 3, that the quickest polymerization reaction wasobtained with d6-DMSO, with a full conversion time within less than 15minutes. The time for reaching full conversion is measured in thepresent example as the time for reaching 97% conversion. D8-THF, whichis the solvent most currently used in the art, yields the secondquickest full conversion rate, with substantially longer conversiontimes of about 840 min (=14 h). C6D6, with a slower start than THF,catches up with similar full conversion times of 840 min (=14 h). Theremaining solvents yield substantially longer full conversion times,largely exceeding 900 min (>15 h), with CD2Cl2 yielding the lowestconversion rate with no observable polymerization after 15 h reactiontime.

Without wishing to be bound by any theory, the surprising resultsobtained with DMSO compared with other, traditionally used solvents, canbe explained as follows. DMSO is a polar aprotic solvent having a ratherhigh donor number (DN) of 125 kJ/mol (=29.9 kcal/mol) according toGutmann's scale. Polar aprotic solvents having a high donor number (DN)according to Gutmann's thermodynamic scale, and having a low acceptornumber (AN) according to Gutmann-Beckett's 31P NMR scale are ofparticular interest for controlling the reactivity of alkoxide speciesused as anionic initiator in the continuous flow polymerization processaccording to the present invention.

Alkoxide species are responsible for the propagation of the anionicpolymerization of ethylene oxide. As illustrated in FIG. 4, the anionicalkoxide species (RO⁻) are associated with a cation (M⁺), selected amongthe alkali and the alkaline-earth elements (generally, Li, Na, K, Cs,Ca, Mg, Be), forming ion pairs. The nature of these ion pairs has astrong impact on the reactivity of the anion, ranging from:

-   -   tight pairs, wherein anionic alkoxide and metal cation remain in        close proximity as illustrated in FIG. 4(d) with a monomer        solvent (21 cex) which is not suitable for the present        invention, such that tight ion pairs are responsible for a low        reactivity, to    -   loose pairs, wherein anionic alkoxide and metal cation are less        attracted to one another, allowing more distance to separate the        anions from the cations, as illustrated in FIG. 4(a) with a        monomer solvent (21) which is suitable for the present        invention, and yielding an increased reactivity of the alkoxide        anion.

As illustrated in FIG. 4(b), a polar aprotic solvent (21DN) having ahigh DN can stabilize metal cations (M+), and hence weaken alkoxidemetal ions pairs. The reactivity of the alkoxide anion is thereforeincreased. A high DN is therefore preferred for increasing thereactivity of the alkoxide anions (RO⁻) with the alkylene oxide monomers(1), thus requiring lower values of pressure (P) and temperature (T),and yielding shorter polymerization times (t).

As illustrated in FIG. 4(c), loose alkoxide metal ions pairs can also beobtained with a polar aprotic solvent (21AN) having a high acceptornumber (AN). Indeed, such solvent can interact very strongly with thealkoxide anions (RO⁻) and form loose ionic pairs. In this case, however,the alkoxide anions (RO⁻) are isolated from the alkylene oxide monomers(1), and higher pressures (P) and temperatures (T) are required forcarrying out the polymerization stage. A polar aprotic solvent suitablefor the present invention therefore preferably has a moderate to lowvalue of AN.

The Gutmann-Beckett Acceptor (AN) and Donor number (DN) are measures ofthe strength of solvents as Lewis acids or bases. The Acceptor Number isbased on the 31P-NMR chemical shift of triethyiphosphine oxide in thesolvent. The Donor Number is based on the heat of reaction between the‘solvent’ and SbCl5 in CH₂ClCH₂Cl.

Some polar aprotic solvents, such as DMSO which yielded such superiorpolymerization kinetics in FIG. 3 over other solvents, are both donorand acceptor, but the donor ability is substantially higher than theacceptor ability. As mentioned supra and listed in Table 1, DMSO has adonor number, DN=125 kJ/mol (=29.9 kcal/mol) and an acceptor number ofAN=19.3. The values of DN and AN of the other solvents tested in FIG. 3are also listed in Table 1.

Based on the above observation, a polar aprotic solvent suitable for useas monomer solvent in the present invention preferably has a donornumber (DN) of at least 120 kJ/mol according to Gutmann's thermodynamicscale. The donor number, DN, preferably does not exceed 250 kJ/mol,preferably does not exceed 200 kJ/mol. The acceptor number (AN) shouldbe low and is preferably not more than 20 according to Gutmann-Beckett'sscale. For example, ethanol has a high value of DN=132 kJ/mol (=31.5kcal/mol) but also a high value of AN=37.9 which makes it less suitableas a monomer solvent (21) than DMSO.

The dielectric constant (E) of a solvent also has an effect onsolubility of anionic components. In a preferred embodiment, the monomersolvent is a polar aprotic solvent having a dielectric constant (E)greater than 30. If an initiator solvent (22) is used for forming aninitiator solution (222) (cf. FIG. 2), it is preferred that theinitiator solvent have the same properties as discussed above withrespect to the monomer solvent (21). Preferably, the initiator solventis the same as the monomer solvent.

Examples of monomer solvents suitable for the present invention include,dimethyl sulfoxide (DMSO), hexamethylphosphoramide (HMPA),tetraalkylureas, or cyclic alkylureas, such as1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone (DMPU), or pyridine.Other solvents with DN- and AN-values comprised within the preferredranges exist, but care must be taken with respect to the toxicity of theselected monomer solvent.

Micro- or Meso-Polymerization Line

The gist of the present invention is to combine, on the one hand,

-   -   (a) the right components including monomer (1), anionic        initiator (2) and, in particular, monomer solvent (21), such as        to yield high intrinsic kinetics with, on the other hand,    -   (b) a polymerization line allowing fast mixing and accurate        control of temperature and pressure.

The combination of these two elements allows rapid polymerization times,below 60 min, at low temperature (including room temperature) and low tomoderate pressures. This has the further benefit of reducing the thermaland mechanical resistance requirements of the polymerization set-up, andthus reducing its cost.

The choice of (a) an appropriate monomer solvent (and monomer andinitiator) has been discussed in detail in the previous sections.According to the present invention, only a continuous flowpolymerization line can reach the requirements defined in point (b)supra. Beside the poorer heat exchanges and mixing efficacy in batchprocesses, because of the high reactivity of the components, such asethylene oxides, the risk of explosions is higher in a batch processthan in a continuous flow process, wherein addition of monomer is spreadover a longer period of time. The polymerization set-up according to thepresent invention must therefore include a continuous flowpolymerization line.

High control of the temperature and high mixing speeds can be betterachieved if the continuous flow polymerization line has reactor modulesand connecting tubes of small dimensions. In particular, ameso-polymerization line can be used, with internal diameters of thereactor modules and connecting tubes of the order of 1 to 20 mm. Highermixing rates and enhanced temperature control were achieved, however,with micro-polymerization lines defined by internal diameters of thesolution and mixing reactor modules comprised between 100 μm and 1000μm, preferably between 200 and 800 μm. The connecting tubes andpolymerization reactor module are preferably composed of capillary tubesof inner diameter comprised between 50 and 700 μm, more preferablybetween 100 and 500 μm. The total inner volume of the solution, mixing,and polymerization reactor modules and connecting tubes can for examplebe comprised between 1 and 10 ml, preferably between 2 and 6 ml.

In a micro-polymerization line, the flow rate of monomer solution (121)into the mixing reactor module (103) can be comprised between 0.1 and 9ml/min, preferably between 0.2 and 1 ml/min. Similarly, the flow rate ofinitiator (2) or initiator solution (222) into the mixing reactor modulemay be comprised between 0.1 and 1 ml/min, preferably between 0.2 and0.5 ml/min. The monomer to initiator molar ratio is preferablycontrolled between 2000 and 20, preferably between 100 and 30, and morepreferably between 50 and 40. The reaction mixture (3) is preferably fedfrom the mixing reactor module (103) through the polymerization reactormodule (104) at a flow rate comprised between 0.1 and 10 ml/min,preferably between 0.3 and 1 ml/min.

The. microstructured polymerization line can be constructed frommicrofluidic modules made of glass, stainless steel, polymericmaterials, ceramics, silicon carbide or a combination of two or severalof the aforementioned materials. The microfluidic modules may includemixers, in-line check valves, pressure regulators, three-way valves,connectors, ferrules, and microreactors connected in series or inparallel through capillaries. The capillaries may be made of stainlesssteel or polymeric materials, such as PEEK, PFA, ETFE or PTFE. Thegeneral design of the micro-polymerization line may include microfluidicchips, coils or tubular fluidic reactors having an internal diametercomprised between 100 and 1000 μm, preferably between 200 and 800 μm.Mixers may be embedded in the microreactor or inserted as independentfluidic elements, such as arrow-head mixers, T-mixers, Y-mixers,cross-junctions or static micromixers, made either of glass, stainlesssteel, polymeric materials and ceramics, or a combination of two orseveral of the aforementioned materials.

In some embodiments, several micro-polymerization lines may befluidically coupled in parallel to the sources of monomer solution (121)and anionic initiator (2) or initiator solution (222) to increaseproductivity. One micro-polymerization line unit is very cheap toproduce and a large array of a number of such units can easily be thusarranged in parallel to reach high production rates.

Example

A continuous-flow polymerization line was produced for thepolymerization of ethylene oxide (1) in the presence of potassiumtert-butoxide (2) in dimethylsulfoxide (21). The setup comprised twofeed solutions for a monomer solution (121) and an initiator solution(222) to a perfluoroalkoxy alcane polymer (PFA) coil reactor (104)through a polyether ether ketone (PEEK) T-mixer (103, 9). High pressureChemyx 6000 pumps (8) were used to deliver the reagents and a 3-wayvalve was inserted before the T-mixer to avoid back flush upon reactoroperation.

A 0.2 M initiator solution (222) of potassium tert-butoxide in dry anddegassed dimethylsulfoxide and a 4 M monomer solution (121) of ethyleneoxide in dry and degassed dimethylsulfoxide were loaded in two 20 ml HPSS syringes, and then installed on HP syringe-pumps, and connected tothe coil reactor via the PEEK T-mixer of internal diameter of 500 μm.The initiator solution was delivered at a flow rate of 0.48 ml/min, andmixed through the PEEK T-mixer with a stream of monomer solution flowingat 0.1 ml/min. The monomer solution was obtained by mixing ethyleneoxide and dimethylsulfoxide in a mixing reactor module (101) fluidicallyconnected upstream of the injection of the initiator solution. The flowrates were set to ensure a monomer to initiator molar ratio of 44.

The homogeneous stream of potassium tert-butoxide and ethylene oxide indimethylsulfoxide was then reacted at 25° C. under 2 bar of pressure ina thermostatized microfluidic polymerization reactor module (104)constructed from 4 m of PFA capillary tubing with a 2 ml internalvolume. The total flow rate through the polymerization reactor modulewas equal to 0.148 ml/min and the residence time was 15 min. The outletof the PFA loop was fluidically connected to a PEEK T-mixer of internaldiameter of 500 μm for downstream processing by quenching with aqueousacetic acid to terminate polymerization. The entire micro-polymerizationline was operated during over 5 h at steady state. The polymerizedethylene oxide thus produced had the following properties: a theoreticalmolecular weight of Mn(Th)=1000 g/mol, assuming 100% polymerization, ameasured molecular weight of Mn(Exp)=900, and a polydispersity ofPDI=1.10. The structural characterization of the polymer by protonnuclear magnetic resonance in deuterated chloroform (=1H NMR (CDCl3))yielded the following chemical shift results, δ, for CH₂-PEG and CH₃moieties, respectively: δ=3.65 (s, 110H, CH₂-PEG) and 1.20 (s, 9H, CH₃)ppm.

The continuous-flow process for polymerization of an alkylene oxide ofthe present invention is highly advantageous. By a proper selection ofthe monomer solvent (21), the process may be carried out at lowtemperature, such as at room temperature and at low to moderatepressure, with short reaction times, typically shorter than one hour,and even shorter than 15 minutes. By carrying out the continuous-flowprocess of the present invention in a micro-polymerization line, theprocess can run optimally by an enhanced control on the reactionconditions, such as temperature, pressure, flow rate and localstoichiometry. The process also permits to obtain a product withwell-defined molecular parameters such as molar mass and polydispersity.The continuous flow process of the present invention provides asubstantially safer handling of alkylene oxides such as ethylene oxide.The process further enables the preparation of homo- orheterobifunctional polyalkylene oxides, such as homo- orheterobifunctional polyethylene oxide. Another advantage is theflexibility to produce polyalkylene oxide on-demand, for specificmolecular parameters and even for small production volumes. Themicro-polymerization line is compact and may be used as a mobile and/ora versatile reactor. This microfluidic process is straightforward,versatile, economic, safe, uses low process temperatures and pressures,and provides high yields and excellent molecular control for theproduction of polymeric architectures from alkylene oxides.

This method overcomes the drawbacks of the prior art including,

-   -   (a) short reaction times are achieved under mild conditions;    -   (b) high operating temperature and pressure conditions are        avoided;    -   (c) time-consuming initiation steps are avoided;    -   (d) homogeneous initiators are privileged, ensuring stability        over long production campaigns without clogging issues;    -   (e) the downstream process is straightforward and enables the        recycling of the solvents    -   (f) only small amounts of ethylene oxide are reacted per unit of        time, therefore significantly reducing industrial risk;    -   (g) the design is very compact, economic, robust and offers full        control over the process parameters;    -   (h) the equipment is simple, and compatible with scale-out or        numbering-up strategies to increase the production scale; and    -   (i) the design is compatible with the production of both homo-        or heterobifunctional aliphatic polyethers.

# feature  1 Alkylene oxide (monomer)  2 Initiator  3 Reaction mixture 5 Polymerized solution  5p Alkylene oxide polymer (of the polymerizedsolution)  5s Solvent of the polymerized solution  6 Functionalizationagent  7 Termination agent  8 Pump  9 Mixer  21 Monomer solvent  21ANHigh AN monomer solvent  21cex Monomer solvent not according to theinvention  21DN High DN monomer solvent  22 Initiator solvent 101Solution reactor module 102 Initiator reactor module 103 Mixing reactormodule 104 Polymerization reactor module 105 Polymer vessel 105pSeparation unit 106 Functionalization reactor module 107 Terminationreactor module 121 Monomer solution 222 Initiator solution

1. A continuous-flow process for the polymerization of an alkylene oxidecomprising: (a) mixing an alkylene oxide (1) with a monomer solvent(12), to form a monomer solution (121), wherein the monomer solvent is apolar aprotic solvent; (b) forming a reaction mixture (3) by mixing themonomer solution with an anionic initiator (2) selected among the alkalior alkaline-earth alkoxides of general formula R-O-M, wherein R is astraight, branched or cyclic alkyl chain, a heterocycle, a glycol or acombination of two or several of these, O is oxygen, and M is orcomprises an alkali, an alkaline-earth metal or salt thereof; (c)allowing the reaction mixture to react for a polymerization time, t,comprised between 1 s and 60 min, at a polymerization temperature, T,comprised between 0 and 100° C., and at a polymerization pressure, P,comprised between 1 and 20 bar above atmospheric pressure, thus forminga polymerized solution (5) comprising a polymerized alkylene oxide (5 p)and a solvent (5 s); and (d) separating the solvent (5 s) from thepolymerized alkylene oxide (5 p).
 2. The continuous-flow processaccording to claim 1, wherein the monomer solvent has: a donor number(DN) of at least 120 kJ/mol according to Gutmann's thermodynamic scale,an acceptor number (AN) of not more than 20 according to GutmannBeckett's scale, a dielectric constant (c) greater than 30, or acombination thereof.
 3. The continuous-flow process according to claim1, wherein the monomer solvent is one of dimethyl sulfoxide (DMSO),hexamethylphosphoramide (HMPA), pyridine, tetraalkylureas, or cyclicalkylureas.
 4. The continuous-flow process according to claim 1, carriedout in a polymerization line, wherein step (a) is carried out in asolution reactor module (101), step (b) in a mixing reactor module (103)in fluid communication with the first reactor module by means of aconnecting tube, and wherein step (c) is carried out in a polymerizationreactor module (104).
 5. The continuous-flow process according to claim4, wherein the continuous-flow process is carried out in a micropolymerization line, wherein the internal diameters of the solution andmixing reactor modules are comprised between 100 μm and 1000 μm andwherein the connecting tube and polymerization reactor module arecapillary tubes of inner diameter comprised between 50 and 700 μm. 6.The continuous-flow process according to claim 5, wherein, The flow rateof the reaction mixture through the polymerization reactor module iscomprised between 0.1 and 10 ml/min; or The flow rate of monomersolution into the mixing reactor module is comprised between 0.1 and 9ml/min; or, The flow rate of initiator into the mixing reactor module iscomprised between 0.1 and 1 ml/min; or a combination thereof.
 7. Thecontinuous-flow process according to claim 5, wherein a total innervolume of the solution, mixing, and polymerization reactor modules andconnecting tubes is comprised between 1 and 10 ml.
 8. Thecontinuous-flow process according to claim 1, wherein a monomer toinitiator molar ratio is comprised between 2000 and
 20. 9. Thecontinuous-flow process according to claim 1, wherein, The alkyleneoxide is present in the monomer solution at a concentration comprisedbetween 0.1 and 10 M; The anionic initiator is fed into the mixingreactor module in a solvent at a concentration comprised between 0.1 and10 M; or a combination thereof.
 10. The continuous-flow processaccording to claim 3, wherein the solution and mixing reactor modulesare equipped with a mixing device comprising one or more of anarrow-head mixer, T-mixer, Y-mixer, cross-junction micromixer, or staticmicromixer, made of glass, stainless steel, polymeric material, orceramics, or a combination of two or more of the foregoing materials.11. The continuous-flow process according to claim 1, further comprisingbetween steps (c) and (d) an additional step of, (c1) functionalizingone or both ends of polymer chains of the polymerized solution byaddition in a functionalization reactor module (106) of one or twofunctionalization agents (6) to the reaction mixture as it polymerizes,or to the polymerized solution; and/or (c2) terminating thepolymerization by addition in a terminating reactor module (107) of atermination agent (7) to the polymerized solution after the time, t;(c3) monitoring the polymerization of the reaction mixture by means ofone or more in line analysis units, preferably comprising at least onespectroscopic analysis unit or a combination of thereof.
 12. Thecontinuous-flow process according to claim 1, wherein: thepolymerization time, t, is comprised between 20 s and 50 min, thepolymerization temperature, T, is comprised between 20 and 50° C., thepolymerization pressure, P, is comprised between 1.5 and 10 bar, aboveatmospheric pressure, or a combination thereof.
 13. The continuous-flowprocess according to claim 1, wherein the alkylene oxide in step (a) isselected from the group consisting of: ethylene oxide, propylene oxideand butylene oxide.
 14. The continuous-flow process according to claim1, wherein M is selected from the group consisting of: lithium, sodiumand potassium.
 15. The continuous-flow process according to claim 1,wherein the anionic initiator is dissolved in a solvent (22) to form aninitiator solution (222) before mixing with the monomer solution in step(b).
 16. The continuous-flow process according to claim 1, wherein themonomer solvent is 1,3-Dimethyl-3,4,5,6-tetrahydro-2-pyrimidinone(DMPU).
 17. The continuous-flow process according to claim 4, whereinthe polymerization reactor module (104) is a tubular reactor forming aserpentine.
 18. The continuous-flow process according to claim 6,wherein a total inner volume of the solution, mixing, and polymerizationreactor modules and connecting tubes is comprised between 1 and 10 ml.19. The continuous-flow process according to claim 4, wherein thesolution and mixing reactor modules are equipped with a mixing devicecomprising one or more of an arrow-head mixer, T-mixer, Y-mixer,cross-junction micromixer, or static micromixer, made of glass,stainless steel, polymeric material, or ceramics, or a combination oftwo or more of the foregoing materials.
 20. The continuous-flow processaccording claim 15, wherein the initiator solvent is the same as themonomer solvent.